Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epigallocatechin-3-gallate (EGCG) is a major constituent of green tea polyphenols. This study was aimed to investigate the possible mechanisms of EGCG-mediated inhibition against apoptosis in rat pheochromocytoma PC12 cells by exposure to CoCl(2). Exposure to CoCl(2) caused the generation of ROS and induced cell death with appearance of apoptotic morphology and DNA fragmentation. However, EGCG rescued the loss of viability in the cells exposed to CoCl(2) and led the reduction of DNA fragmentation and sub-G(1) fraction of cell cycle. Also, EGCG attenuated the CoCl(2)-induced disruption of mitochondrial membrane potential (DeltaPsim), release of cytochrome c from the mitochondria to cytosol and abolished the CoCl(2)-stimulated activities of the caspase cascades, caspase-9 and caspase-3. In addition, EGCG ameliorated the increase in the Bax to Bcl-2 ratio, a marker of apoptosis proceeding, induced by CoCl(2) treatment. Taken together, the present results suggest that EGCG inhibit the CoCl(2)-induced apoptosis of PC12 cells through the mitochondria-mediated apoptosis pathway involved in modulating the Bcl-2 family.
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PMID:Inhibition by epigallocatechin gallate of CoCl2-induced apoptosis in rat PC12 cells. 1724 Apr 4

4-Hydroxynonenal (HNE) is one of the most abundant aldehyde components of ox-LDL and it exerts various effects on intracellular and extracellular signaling cascades. In this mini-review, a brief synopsis of HNE-modulated signaling pathways will be presented mainly focused on cell death, including recent studies from our laboratory. The results of a number of studies demonstrate the ability of HNE to induce apoptosis and ROS formation in a dose-dependent manner. Several signaling pathways have been shown to be modulated by HNE, including MAP kinases, PKC isoforms, cell-cycle regulators, receptor tyrosine kinases and caspases. In order to get insight into the mechanisms of apoptotic response by HNE, MAP kinase and caspase activation pathways have been studied in 3T3 fibroblasts; HNE induced early activation of JNK and p38 proteins but down-regulated the basal activity of ERK-1/2. We have shown that HNE-induced release of cytochrome c from mitochondria, caspase-9 and caspase-3 activation. Activation of AP-1 along with increased c-Jun and phospho-c-Jun levels could be inhibited by pretreatment of cells with certain molecules such as resveratrol. Additionally, overexpression of dominant negative c-Jun and JNK1 in 3T3 fibroblasts prevented HNE-induced apoptosis, which indicated a role for JNK-c-Jun/AP-1 pathway. JNK-dependent induction of c-Jun/AP-1 activation data in the literature indicates a critical potential role for JNK in the cellular response against toxic products of lipid peroxidation.
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PMID:Apoptosis signalling by 4-hydroxynonenal: a role for JNK-c-Jun/AP-1 pathway. 1726 5

Cadmium immunotoxicity in rodents is primarily characterized by marked thymic damage and splenomegaly. To understand the toxicity of Cd on lymphoid cells in vivo, a single dose of Cd as CdCl2 (1.8 mg/kg, i.p.) was administered to male BALB/c mice and cytotoxicity (MTT assay), oxidative stress indicators (glutathione, reactive oxygen species) and apoptotic markers (mitochondrial membrane potential, caspase-3 activity, phosphatidylserine externalization, apoptotic DNA, intranucleosomal DNA fragmentation) were assessed in thymic and splenic single cell suspensions, at various time intervals. Lowering of body weight gain and cellularity and a loss in cell viability was seen in the Cd treated mice. The earliest significant increase in ROS at 18 h, followed by mitochondrial membrane depolarization, caspase-3 activation and GSH depletion at 24h in spleen and later at 48 h in thymus, strongly implicate the possible involvement of ROS. A pronounced inhibition of cell proliferative response at 48 h and 72 h may also be linked to Cd induced apoptosis. The morphological alterations including thymic cortical cell depletion and an increase in red pulp with diminished white pulp in spleen were observed at 48 h and beyond. The splenic cells appeared more susceptible than thymus cells to the adverse effects of Cd. The present study, therefore, demonstrates potentiation of oxidative stress followed by mitochondrial-caspase dependent apoptotic pathway. This may, in part, be responsible for causing suppression of cell proliferative response, thymic atrophy and splenomegaly.
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PMID:Role of oxidative stress and apoptosis in cadmium induced thymic atrophy and splenomegaly in mice. 1726 44

This study investigates the mechanism of cell death induced by cadmium (Cd) in Chinese hamster ovary (CHO) cells. Cells exposed to 4 microM Cd for 24 h did not show signs of apoptosis, such as DNA fragmentation and caspase-3 activation. The pro-apoptotic (Bax) or anti-apoptotic (Bcl-2 and Bcl-xL) protein levels in the Bcl-2 family were not altered. However, an increase in propidium iodide uptake and depletion of ATP, characteristics of necrotic cell death, were observed. Cd treatment increased the intracellular calcium (Ca2+) level. Removal of the Ca2+ by a chelator, BAPTA-AM, efficiently inhibited Cd-induced necrosis. The increased Ca2+ subsequently mediated calpain activation and intracellular ROS production. Calpains then triggered mitochondrial depolarization resulting in cell necrosis. Cyclosporin A, an inhibitor of mitochondrial permeability transition, recovered the membrane potential and reduced the necrotic effect. The generated ROS reduced basal NF-kappaB activity and led cells to necrosis. An increase of NF-kappaB activity by its activator, PMA, attenuated Cd-induced necrosis. Calpains and ROS act cooperatively in this process. The calpain inhibitor and the ROS scavenger synergistically inhibited Cd-induced necrosis. Results in this study suggest that Cd stimulates Ca2+-dependent necrosis in CHO cells through two separate pathways. It reduces mitochondrial membrane potential by activating calpain and inhibits NF-kappaB activity by increasing the ROS level.
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PMID:Cadmium induces Ca2+-dependent necrotic cell death through calpain-triggered mitochondrial depolarization and reactive oxygen species-mediated inhibition of nuclear factor-kappaB activity. 1732 76

Recently, considerable attention has been focused on dietary manipulation of oxidative and/or nitrosative damage on neuronal cells. In this article, a neuroprotective effect of plant (Saengshik) extracts was investigated. Rat pheochromocytoma (PC12), cells treated with beta-amyloid underwent apoptotic death as determined by positive in situ terminal end-labeling (TUNEL staining), decreased mitochondrial transmembrane potential, and elevated caspase-3 activity co-occurring with enhanced MDA accumulation and the reduction of GSH levels. Saengshik pretreatment attenuated beta-amyloid-induced apoptosis in PC12 cells possibly by inhibiting mitochondrial dysfunction and exerting antioxidant properties. Saengshik pretreatment inhibited the loss of mitochondrial membrane potentials and reduced the activation of caspase-3. The in vitro antioxidant activities of Saengshik extracts were verified by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) method and superoxide dismutase (SOD) mimetic activity. In beta-amyloid-challenged PC12 cells, Saengshik prevented the production of ROS, decreased the level of MDA, and elevated GSH. The potential of Saengshik as one of the neuroprotective regimens has been suggested through this article, and the combination with defined pharmaceuticals or other dietary antioxidants may provide a better therapeutic or preventive advantage for the management of Alzheimer's disease.
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PMID:Attenuation of Abeta-induced apoptosis of plant extract (Saengshik) mediated by the inhibition of mitochondrial dysfunction and antioxidative effect. 1740 52

tert-Butylhydroperoxide has been reported to inhibit growth and induce apoptosis in number of cell types, but little is known about the molecular mechanism mediating these effects. In the present study, we determined the molecular pathways that lead to apoptosis after treatment of cells with t-BOOH. The cells were exposed to different concentrations of t-BOOH (100-750 microM) for 1-4 h and various parameters such as cytotoxicity, ROS (reactive oxygen species) generation, MMP (mitochondrial membrane potential), intracellular Ca++ levels and expression of various proteins involved in apoptosis were determined. Exposure of U-937 cells to t-BOOH induced cytotoxicity in a time dependent manner with about 50% toxicity at 400 microM t-BOOH in 4h. t-BOOH treatment resulted in a time dependent increase in reactive oxygen species levels, Ca++ influx and annexin V positive cells. There was a significant fall in MMP following exposure to t-BOOH with time. t-BOOH treatment of U-937 cells leads to apoptosis, which is accompanied by activation of caspase-3. The caspase-3 inhibitor (Ac-DEVD-CHO) inhibits the cytotoxicity induced by t-BOOH, indicating a direct link between caspase-3 activation and cell death. This activation of apoptosis is accompanied by release of cytochrome c, down regulation of anti-apoptotic protein Bcl-2 levels with concurrent increase in pro-apoptotic proteins Bax and Bad levels. These observations indicate that t-BOOH induces cell death in U-937 macrophages by apoptosis, which is mediated through mitochondrial pathway.
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PMID:Mechanism of tert-butylhydroperoxide induced cytotoxicity in U-937 macrophages by alteration of mitochondrial function and generation of ROS. 1741

Pyrogallol as a catechin compound has been employed as an O(2)(*-) generator and often used to investigate the role of ROS in the biological system. Here, we investigated the in vitro effect of pyrogallol on cell growth, cell cycle and apoptosis in As4.1 juxtaglomerular cells. Dose-dependent inhibition of cell growth was observed with IC(50) of about 60 microM for 48 h using MTT assay. Pyrogallol (100 microM) did not alter intracellular H(2)O(2) level and catalase activity, but increased the intracellular O(2)(-) level and decreased SOD activity in As4.1 cells. DNA flow cytometric analysis indicated that 50 and 100 microM pyrogallol significantly increased G2 phase cells as compared with those of pyrogallol-untreated cells. Also, pyrogallol induced apoptosis as evidenced by flow cytometric detection of sub-G1 DNA content, annexin V binding assay and DAPI staining. This apoptosis process was accompanied with the loss of mitochondrial transmembrane potential (DeltaPsi(m)), Bcl-2 decrease, caspase-3 activation and PARP cleavage. Pan caspase inhibitor (Z-VAD) could significantly rescue As4.1 cells from pyrogallol-induced cell death. But, the inhibitors of caspase-3, caspase-8, and caspase-9 did not prevent apoptotic events in pyrogallol-treated As4.1 cells. Taken together, we have demonstrated that an ROS inducer, pyrogallol inhibits the growth of As4.1 JG cells via cell cycle arrest and apoptosis, and suggest that the compound exhibits an anti-proliferative efficacy on these cells.
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PMID:Pyrogallol, ROS generator inhibits As4.1 juxtaglomerular cells via cell cycle arrest of G2 phase and apoptosis. 1744 75

Growth inhibitory effects of 15-lipoxygenase-1 [13-(S)-HPODE and 13-(S)-HODE] and 15-lipoxygenase-2 [15-(S)-HPETE and 15-(S)-HETE] (15-LOX-1 and LOX-2) metabolites and the underlying mechanisms were studied on chronic myeloid leukemia cell line (K-562). The hydroperoxy metabolites, 15-(S)-HPETE and 13-(S)-HPODE rapidly inhibited the growth of K-562 cells by 3h with IC(50) values, 10 and 15microM, respectively. In contrast, the hydroxy metabolite of 15-LOX-2, 15-(S)-HETE, showed 50% inhibition only at 40microM by 6h and 13-(S)-HODE, hydroxy metabolite of 15-LOX-1, showed no significant effect up to 160microM. The cells exposed to 10microM of 15-(S)-HPETE and 40microM of 15-(S)-HETE showed typical apoptotic features like release of cytochrome c, caspase-3 activation and PARP-1 (poly(ADP) ribose polymerase-1) cleavage. A flow cytometry based DCFH-DA analysis and inhibitory studies with DPI, a pharmacological inhibitor of NADPH oxidase, NAC (N-acetyl cysteine) and GSH revealed that NADPH oxidase-mediated generation of ROS is responsible for caspase-3 activation and subsequent induction of apoptosis in the K-562 cell line.
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PMID:Effect of 15-lipoxygenase metabolites, 15-(S)-HPETE and 15-(S)-HETE on chronic myelogenous leukemia cell line K-562: reactive oxygen species (ROS) mediate caspase-dependent apoptosis. 1751 76

A fraction of attenuated Leishmanial lipid (ALL) rich in sphingolipids, previously shown to have apoptosis inducing activity in mouse melanoma (B16F10) and human melanoma (A375) cells, was resolved to isolate the bioactive sphingolipid. The mechanism of apoptosis induction by this bioactive attenuated Leishmanial sphingolipid (ALSL) was studied in A375 cells. Apoptosis induced by ALSL in A375 cells was found to be dose and time-dependent. Exposure of cells to ALSL resulted in a rapid increase in reactive oxygen species generation. Pretreatment of cells with the antioxidant N-acetyl-cystein reduced ROS generation and attenuated apoptosis induced by ALSL. Again, ALSL sensitization resulted in the activation of caspase-3 and -9 but not caspase-8. However, inhibitors of these caspases could not protect the cells completely from ALSL-induced apoptosis. N-acetyl-cystein pretreatment was again found to attenuate the activation of caspase-3 and -9. ALSL treatment also resulted in the alteration of mitochondrial membrane potential, and release of pro-apoptotic factors such as cytochrome c and apoptosis inducing factor (AIF) from mitochondria. Furthermore, c-Jun N-terminal kinase was activated that resulted in apoptosis of A375 cells, whereas p38 MAPK was activated to counteract the stress generated in cells in response to ALSL treatment. Taken together, our results indicate that ALSL-induced apoptosis of A375 cells is mediated by both mitochondrial caspase-dependent and -independent pathways and it involves ROS and JNK activation in the mitogen-activated protein kinase cascade.
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PMID:Attenuated Leishmanial sphingolipid induces apoptosis in A375 human melanoma cell via both caspase-dependent and -independent pathways. 1753 Jan 91

Morphine is recommended as a first-line opioid analgesic in the pain management of cancer patients. Accumulating evidence shows that morphine has anti-apoptotic activity, but its impact on the therapeutic applications of antineoplastic drugs is not well known. The present study was undertaken to test the hypothesis that morphine might antagonize the pro-apoptotic activity of DOX (doxorubicin), a commonly used antitumour drug for the treatment of neuroblastoma, in cultured SH-SY5Y cells. In the present study we demonstrated that morphine suppressed DOX-induced inhibition of cell proliferation and programmed cell death in a concentration-dependent, and naloxone as well as pertussis toxin-irreversible, manner. Further studies showed that morphine inhibited ROS (reactive oxygen species) generation, and prevented DOX-mediated caspase-3 activation, cytochrome c release and changes of Bax and Bcl-2 protein expression. The antioxidant NAC (N-acetylcysteine) also showed the same effects as morphine on DOX-induced ROS generation, caspase-3 activation and cytochrome c release and changes in Bax (Bcl-2-associated X protein) and Bcl-2 protein expression. Additionally, morphine was found to suppress DOX-induced NF-kappaB (nuclear factor kappaB) transcriptional activation via a reduction of IkappaBalpha (inhibitor of nuclear factor kappaB) degradation. These present findings support the hypothesis that morphine can inhibit DOX-induced neuroblastoma cell apoptosis by the inhibition of ROS generation and mitochondrial cytochrome c release, as well as by blockade of NF-kappaB transcriptional activation, and suggests that morphine might have an impact on the antitumour efficiency of DOX.
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PMID:Morphine inhibits doxorubicin-induced reactive oxygen species generation and nuclear factor kappaB transcriptional activation in neuroblastoma SH-SY5Y cells. 1754 80


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